We have implemented five drug-like filters, based on 1D and 2D molecular descriptors, and applied them to characterize the drug-like properties of commercially available chemical compounds. In addition to previously published filters (Lipinski and Veber), we implemented a filter for medicinal chemistry tractability based on lists of chemical features drawn up by a panel of medicinal chemists. A filter based on the modeling of aqueous solubility (>1 microM) was derived in-house, as well as another based on the modeling of Caco-2 passive membrane permeability (>10 nm/s). A library of 2.7 million compounds was collated from the 23 compound suppliers and analyzed with these filters, highlighting a tendency toward highly lipophilic compounds. The library contains 1.6 M unique structures, of which 37% (607,223) passed all five drug-like filters. None of the 23 suppliers provides all the members of the drug-like subset, emphasizing the benefit of considering compounds from various compound suppliers as a source of diversity for drug discovery.

Journal Article↗

PubMedDate not supplied

Thermosensitivity of multidrug-resistant human gastric and pancreatic carcinoma cells.

Often, tumour cells acquire drug resistance phenotypes, which include the classical multidrug resistance (MDR) phenomenon accompanied by the synthesis of the P-glycoprotein (Pgp) and atypical MDR phenotypes mediated by different, in part unknown, mechanisms. To investigate the susceptibility of tumour cells exhibiting different kinds of MDR to treatment with heat, the hyperthermic survival of established human gastric and pancreatic carcinoma cell lines were studied and sublines exhibiting a classical and an atypical MDR phenotype were derived, respectively. Arrhenius analysis of this panel of gastrointestinal tumour cells revealed that both the classical and the atypical MDR variants exhibited no breaking points (T*) in contrast to the parent tumour cells. The activation enthalpies E(A) were about 40% lower at T > T* in comparison to the E(A) at lower temperatures. Classical MDR variants of both gastrointestinal tumour cell types exhibited a similar E(A) value, whereas the E(A) of atypical MDR gastric carcinoma cells was 1.6-fold higher than the E(A) of corresponding pancreatic carcinoma cells. In comparison to the parent lines, the drug resistant variants exhibited a 2.1-fold (gastric carcinoma, classical MDR), 2.7-fold (gastric carcinoma, atypical MDR) and 1.4-fold (pancreatic carcinoma, classical MDR) increase of activation enthalpies and a nearby unchanged E(A) in pancreatic carcinoma cells exhibiting an atypical MDR.

Antineoplastic Agents↗

PubMedDate not supplied

Inductive heating of ferrimagnetic particles and magnetic fluids: physical evaluation of their potential for hyperthermia.

The potential of colloidal subdomain ferrite particle suspensions (SDP) ('magnetic fluids'), exposed to an alternating magnetic field, is evaluated for hyperthermia. Power absorption measurements of different magnetic fluids are presented in comparison to multidomain ferrite particles (MDP). Variations with frequency as well as magnetic field strength have been investigated. The experimental results clearly indicate a definite superiority of even non-optimized magnetic fluids over MDP ferrites regarding their specific absorption rate (SAR). Based on the work of Shliomis et al. (1990) and Hanson (1991), a solid-state physical model is applied to explain the specific properties of magnetic fluids with respect to a possible use in hyperthermia. The experimentally determined SAR data on magnetic fluids are used to estimate the heating capabilities of a magnetic induction heating technique assuming typical human dimensions and tissue parameters. It is considered that for a moderate concentration of 5 mg ferrite per gram tumour (i.e. 0.5% w/w) and clinically acceptable magnetic fields, intratumoral power absorption is comparable to RF heating with local applicators and superior to regional RF heating (by comparison with clinical SAR measurements from regional and local hyperthermia treatments). Owing to the high particle density per volume, inductive heating by magnetic fluids can improve temperature distributions in critical regions. Furthermore, localized application of magnetic fluids in a tumour might be easier and less traumatic than interstitial implantation techniques.

Colloids↗

PubMedDate not supplied

Development and testing of SAR-visualizing phantoms for quality control in RF hyperthermia.

A new prototype of an elliptical standard phantom with fat-equivalent walls and a lamp matrix for SAR (specific absorption rate) visualization has been developed. This paper outlines the manufacture of solid components based upon either polyester resin or epoxy resin, as well as the adjustment of their electrical conditions (epsilon r, sigma) by admixtures of carbon and/or aluminium powder. Visualizing sensors (LED = light-emitting diodes, miniature lamps) are evaluated with respect to their transformation of electric field strength into light. Standard SAR patterns of the hyperthermia system BSD-2000 have been semiquantitatively assessed by the visualizing technique (power stepping method) and quantitatively by E field sensor scans. Extracted iso-SAR distributions are in good agreement with E field sensor scans performed with a lamp sensor coupled to a fibre or using a dipole probe with high resistive leads. The requirement for periodic quality control of SAR patterns of RF (radio frequency) hyperthermia systems is demonstrated. Comparisons between techniques are given, specifically with respect to the LED phantom of Schneider and van Dijk.

Electronics, Medical↗

PubMedDate not supplied

Cellular uptake of magnetic fluid particles and their effects on human adenocarcinoma cells exposed to AC magnetic fields in vitro.

Suspensions of coated superparamagnetic particles (magnetic fluids, MF) in AC magnetic fields have a pronounced specific absorption rate (SAR) per mass compared to multidomain particles. The aim of the present study was to investigate cellular uptake and the biological effects of AC magnetic field excited bio-compatible magnetic fluids on human carcinoma cells in vitro. One of the fluids tested was a dextran magnetite, which has a very low cyto-toxicity with survival fractions (SF) between 0.8 and 0.9 at concentrations of up to 5 mg ferrite per ml. Human carcinoma cells intracellularly accumulate up to 1 pg ferrite/cell which has been demonstrated by electron microscopy (TEM), X-ray spectroscopy and measurements of intracellular iron. It has been shown that the ferrite core is not altered intracellularly, but many of the dextran shells are degraded which yields particle chains and other aggregates observed in TEM. Semi-solid pellets of the tumour cells were treated with AC magnetic fields (520 kHz, 4-12.5 kA/m) or waterbath hyperthermia at 43 and 45 degrees C, in presence of extracellular and/or intracellular magnetic fluid particles. Although MF heating is produced from individual particles, the survival fractions of MF heated and water bath heated cells are equal. In fact, the extracellular MF particle distribution is homogeneous enough to obtain similar inactivation. In contrast to earlier reports intracellular dextran magnetite particles in AC magnetic fields did not induce cell inactivation. Since the amount of intracellular ferrite should be indeed large enough for cell inactivation, the loss of dextran shells is most probably the main cause of limited effectiveness of the intracellular magnetite particles. The present work has demonstrated that: (1) MFH is able to inactivate tumour cells in vitro to at least the same extent as water bath hyperthermia; and (2) that there is a sensitizer effect of ferrofluids at 43 degrees C probably caused by free ferric ions which induce oxidative stress; and (3) that there is no cytotoxic effect of intracellular dextran magnetite particles 30-180 min excited with AC magnetic fields used in this study. For the new method the term 'magnetic fluid hyperthermia (MFH)' is proposed.

Adenocarcinoma↗

PubMedDate not supplied

Effects of magnetic fluid hyperthermia (MFH) on C3H mammary carcinoma in vivo.

Magnetic fluids (MF) have a potential for hyperthermia due to their good power absorption capabilities. Recent in vitro experiments with the so-called 'Magnetic Fluid Hyperthermia (MFH)' have shown that human tumours cells are homogeneously inactivated after AC magnetic field excitation of extracellular MF. The aim of the present study was the evaluation of a high dose MFH on intramuscularly implanted mammary carcinoma of the mouse. The tumours originated from initial in vivo passages of a spontaneous parent tumour. Because of larger variations of tumour growth in this rather primary model, logistic regression of non-averaged volumes was performed for each treatment modality. All growing tumours were randomized 30 days after transplantation (day of treatment) with an overall size distribution between 120-400 mm3. An intratumoural steady state temperature of 47 +/- 1.0 degrees C was maintained for 30 minutes with whole-body AC magnetic fields of 6-12.5 kA/m at 520 kHz. The magnetic fluid was #P6, which is a high biocompatible dextran magnetite. #P6 was given intratumourally (1.5 x 10(-2) mg ferrite/mm3) 20-30 minutes before excitation and was combined with magnetic targeting (50 mT), which yielded a 2.5-fold enhancement of the intratumoural iron concentration. Histological examinations of tumour tissue after intralesional ferrofluid administration alone indicated deep infiltration of the fluid into the carcinoma tissue, but no evidence of tissue damage as compared with untreated controls. In contrast, widespread tumour necrosis was observed after MFH. After application of either dextran or ferrofluid alone (no difference, p = 0.665), tumour growth was slightly delayed in comparison with untreated controls (p < 0.001). In contrast to the good fit of the controls (R = 0.92-0.87), tumour growth after MFH was much more heterogeneous; some tumours showed no evidence for regrowth at 50 days whereas others had grown quite readily. This most probably reflected the critical problem of homogeneity of the intratumoural MF distribution, which was also confirmed qualitatively by Magnetic Resonance Imaging (MRI), heterogeneous pigmentation of MFH treated tumours, and up to 1 degree C differences between temperature probes in the same tumour during AC magnetic field application. However, a quantitative comparison between intratumoural MF-heterogeneity and tumour response could not be performed in this study. Despite these current limitations, the regression analysis of the MFH data yielded a smaller tumour volume of about 1000 mm3 at 50 days growth time in contrast to all three controls. In conclusion, encouraging results have been obtained, which show, that one single high dose MFH is already able to induce local tumour control in many cases within 30 days after treatment. To overcome the uncertainties of intratumoural MF heterogeneity, advanced intralesional application methods are currently under development.

Animals↗

PubMedDate not supplied

Heat response of HT29 cells depends strongly on perfusion--a 31P NMR spectroscopy, HPLC and cell survival analysis.

A model system of perfused human colon adenocarcinoma cells (HT29) encapsulated in alginate was used to examine metabolic response to heat therapy with 31P NMR spectroscopy, HPLC and cell survival analysis. The presented data show, that perfused (medium flow during hyperthermia) and non-perfused (no medium flow during hyperthermia) cells are very difficult in their sensitivity to hyperthermia. Under equivalent experimental conditions with respect to medium pH, oxygen and nutrient concentration, encapsulated perfused HT 29 cells display a significantly lower thermal sensitivity than non-perfused cells. This reduced sensitivity of perfused cells is characterized by an increased cell survival and relative ATP concentration, and reduced drop of the NTP/Pi ratio in the long-term follow up towards zero. The relative ATP concentration determined by HPLC after hyperthermia is correlated with the clonogenic survival fraction. There is a direct relationship, depending on the specific experimental conditions (perfused, non-perfused). For perfused cells only a slight dependency of survival and relative ATP concentration on heat dose is observed. In consequence, the correlation between survival and relative ATP concentration is weak, described by log(SFperf) = 0.7*[ATP-12.4, R2 = 0.79, p < 0.04. For non-perfused cells the correlation is stronger resulting in a relationship of log(SFno perf) = 0.6*[ATP]-9.0, R2 = 0.98, p < 0.0002. Altogether, the presented data suggest that the relative ATP concentration measured by HPLC after hyperthermia might be predictive for cell survival. On the other hand, a dependence between cell survival and long-term changes of NTP/Pi has been found. The results confirm the importance of tumour perfusion for hyperthermia-induced metabolic changes and cytotoxicity and therefore, for the therapeutic outcome.

Adenosine Triphosphate↗

PubMedDate not supplied

Arrhenius analysis of the thermal response of human colonic adenocarcinoma cells in vitro using the multi-target, single-hit and the linear-quadratic model.

In order to compare the intrinsic thermal sensitivity of different malignant cell lines the multi-target, single-hit model has been widely accepted. It is even applied in clinical hyperthermia by the so-called thermal isoeffect dose (TID) concept originated from this model. The second model which is preferentially used to describe radiation survival curves is the linear-quadratic (LQ) model which can be also applied to thermal response. Interestingly, no breaking point and different activation energies are obtained with this model. In the present paper we demonstrate this discrepancy with the two human colonic adenocarcinoma cell lines WiDr and SW620. Our results further validate the already earlier published persuasion, that neither the multi-target, single-hit model, nor the LQ model are adequate to describe hyperthermic survival. Since both models give completely different results, further data aquisition of isoeffect factors, breaking points and activation enthalpies based on the multi-target, single-hit model only, is unprofitable until advanced models of thermal inactivation have been developed.

Adenocarcinoma↗

PubMedDate not supplied

Solid materials with high dielectric constants for hyperthermia applications.

The manufacture of solid components with high permittivities epsilon r of 1-100 and differing conductivities sigma of 0-1.0 S/m has practical significance for fabricating applicators and phantoms in radiofrequency hyperthermia. For this purpose, various plastics (resins, polyurethane and silicone) were combined with additives (graphite and metal powder) and tested to assess their radiofrequency and mechanical characteristics and to identify manufacturing problems. Most of the plastics could be made highly dielectric and conductive by adding graphite in the range of muscle tissue (i.e. epsilon r approximately 80, sigma approximately 0.8 S/m). However, there are major differences between the materials with respect to mechanical behaviour, durability, feasibility of manufacture, and reproducibility. Manufacturing water-equivalent plastics (low conductivity sigma < 0.05 S/m and epsilon r value of 70-80) is particularly difficult. A less filled polyester resin in which concentration of brass powder can achieve an epsilon r value of up to 100 at low conductivity proved to be the only suitable medium. Such a plastic can be used for future applicator designs. Other materials of interest include plastics equivalent to lossy media (e.g. sigma = 0.45-0.55 S/m, epsilon r = 70-80), fat-equivalent plastics (polyurethane with graphite) and higher dielectric flexible plastics (silicone with brass powder).

Electric Conductivity↗

PubMedDate not supplied

Whither CPD? Let common sense prevail.

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Attitude of Health Personnel↗

PubMedDate not supplied

Miracle microscope offers hope.

There are thousands of instruments and machines that physicians and health care professionals use for medical treatment. The great majority help perform tests and treatments that are fairly routine. But once in a while something distinctively different and exciting comes along, something like the MKM (Microscope Koordinate Manipulator) robotic microscope.

Adult↗

PubMedDate not supplied

[Degradation of anthraquinone blue by Trametes trogii].

The ability of the white rot fungus Trametes trogii BAFC 463 (high producer of ligninolytic enzymes, especially laccase and manganese peroxidase) to degrade the dye anthraquinone blue, refractory to bacterial attack, was evaluated. Both tropho- and idiophasic T. trogii cultures in synthetic medium (glucose/asparagine) and complex medium (malt extract/glucose) were able to transform up to 88% dye in 4 hours. The activity of laccase, an oxygen-dependent phenoloxidase which was present at high levels in all the conditions assayed, might be related to the ability of the fungus to degrade the colorant. This is supported by the fact that in bioreactor experiences carried out at pH 4.5 the addition of anthraquinone blue caused a decrease in the levels of soluble oxygen. However, although high levels of laccase were produced at pH 7.5, the enzyme was not active, and neither dye transformation nor loss in the levels of soluble oxygen were quantified.

Anthraquinones↗

PubMedDate not supplied

Mechanical low back pain: etiology and conservative management.

Explore the source record for details and available documents.

Chiropractic↗